Epigenetic Regulation of Cell Type–Specific Expression Patterns in the Human Mammary Epithelium

Abstract

Differentiation is an epigenetic program that involves the gradual loss of pluripotency and acquisition of cell type–specific features. Understanding these processes requires genome-wide analysis of epigenetic and gene expression profiles, which have been challenging in primary tissue samples due to limited numbers of cells available. Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, as well as gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type–specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation.

The epigenome of AML stem and progenitor cells

“…Similar data were described for breast cell differentiation. 33 These findings are consistent with a recent hypothesis that histone modifications indicate, instead of tight regulation of transcription, fine-tuning of transcription to ensure a certain chromatin state that allows the proper execution of transcriptional control. 40 Overall, our results suggest that genome-wide histone modifications are important to determine stem or progenitor cell states in AML.…”

“…23,33 Our data suggest that histone modifications also mediate stem cell to differentiated cell transition in cancer. In general we found as expected that K4 marks are concentrated at TSS whereas K27 marks are distributed broadly.…”

Upregulation of miR-196a andHOTAIRDrive Malignant Character in Gastrointestinal Stromal Tumors

“…Trimethylated Histone H3 lysine 4 (H3K4me3) was analyzed using chromatin immunoprecipitation (ChIP) as described previously (13,14). Details of the experimental procedures are provided in the Supplementary Methods.…”

Tumor microenvironment and breast cancer progression

“…25 However, they focused mainly on tumor epithelial cells and there was little in-depth study on the potential involvement in tumor progression of other epithelial and myoepithelial cells or of the stroma. 26 Other studies have reported somatic genetic alterations, including gene copy number changes, microsatellite instability (MSI) and point mutations in tumor suppressor genes, and oncogenes in breast tumor stroma. [27][28][29][30][31][32][33][34] In 2004, Fukino 31 compared global genomic alterations between carcinomatous epithelium and tumor stroma from 134 sporadic invasive breast carcinoma samples.…”